U.S. patent application number 17/627042 was filed with the patent office on 2022-09-01 for pharmaceutical composition of temozolomide.
This patent application is currently assigned to INTAS PHARMACEUTICALS LTD.. The applicant listed for this patent is INTAS PHARMACEUTICALS LTD.. Invention is credited to Jwalant Vijaybhai DESAI, Ashutosh JAMLOKI, Venkataramana NAIDU, Mayank SAXENA.
Application Number | 20220273646 17/627042 |
Document ID | / |
Family ID | 1000006379851 |
Filed Date | 2022-09-01 |
United States Patent
Application |
20220273646 |
Kind Code |
A1 |
DESAI; Jwalant Vijaybhai ;
et al. |
September 1, 2022 |
PHARMACEUTICAL COMPOSITION OF TEMOZOLOMIDE
Abstract
A stable pharmaceutical composition of temozolomide for oral
administration. The pharmaceutical composition is in the form of
powder for oral suspension, wherein the said powder is
reconstituted with a liquid vehicle just before administration.
Further the invention relates to process for the preparation of
said pharmaceutical composition and its packaging in individual
doses.
Inventors: |
DESAI; Jwalant Vijaybhai;
(Sanand Ahmedabad, Gujarat, IN) ; SAXENA; Mayank;
(Sanand Ahmedabad, Gujarat, IN) ; JAMLOKI; Ashutosh;
(Sanand Ahmedabad, Gujarat, IN) ; NAIDU;
Venkataramana; (Sanand Ahmedabad, Gujarat, IN) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
INTAS PHARMACEUTICALS LTD. |
Thaltej, Gujarat Ahmedabad |
|
IN |
|
|
Assignee: |
INTAS PHARMACEUTICALS LTD.
Thaltej, Gujarat Ahmedabad
IN
|
Family ID: |
1000006379851 |
Appl. No.: |
17/627042 |
Filed: |
July 16, 2020 |
PCT Filed: |
July 16, 2020 |
PCT NO: |
PCT/IB2020/056679 |
371 Date: |
January 13, 2022 |
Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 47/10 20130101;
A61K 47/12 20130101; A61K 47/02 20130101; A61K 31/495 20130101;
A61K 9/0095 20130101 |
International
Class: |
A61K 31/495 20060101
A61K031/495; A61K 47/12 20060101 A61K047/12; A61K 9/00 20060101
A61K009/00; A61K 47/10 20060101 A61K047/10; A61K 47/02 20060101
A61K047/02 |
Foreign Application Data
Date |
Code |
Application Number |
Jul 16, 2019 |
IN |
201921028629 |
Claims
1. A pharmaceutical composition of temozolomide comprising (a) a
powder blend of temozolomide and pharmaceutically acceptable
excipients, (b) a liquid vehicle, wherein the said composition is
administered in the form of a powder for oral suspension wherein
the said powder is reconstituted with a liquid vehicle just before
administration.
2. The oral suspension as claimed in claim 1, wherein said
pharmaceutically acceptable excipient are selected from diluent,
stabilizer, glidant, optionally sweetener, and flavoring agent or
mixtures thereof.
3. The oral suspension as claimed in claim 2, wherein diluent is
selected from the group consisting of lactose, calcium phosphate,
calcium sulfate, calcium carbonate, mannitol, xylitol, sucrose,
maltose, fructose, dextrose, maltodextrin or mixtures thereof
4. The oral suspension as claimed in claim 2, wherein stabilizer is
tartaric acid.
5. The oral suspension as claimed in claim 2, wherein glidant is
selected from the group consisting of colloidal silicon dioxide,
magnesium silicate, starch, talc, tribasic calcium phosphate,
stearic acid, palmitic acid or mixtures thereof.
6. The oral suspension as claimed in claim 1, wherein a liquid
vehicle comprising suspending agent, solvent, optionally
preservative, optionally sweetener or optionally flavoring
agent.
7. The oral suspension as claimed in claim 1, wherein the amount of
Temozolomide is 30% to 60% of total powder composition.
8. The oral suspension as claimed in claim 1, wherein the said
composition packaged as single-dose or multi-dose administration to
adults as well as pediatric patients
9. The oral suspension as claimed in claim 1, wherein the said
powder does not contain more than 5% of total impurity of
temozolomide and assay of temozolomide is in range of 90-110% in
the composition, when stored at 40.degree. C./75% RH for at least
one months.
10. A process for the preparation of a stable oral pharmaceutical
composition comprising temozolomide and one or more
pharmaceutically acceptable excipients, wherein the said
composition is in the form of a powder for oral suspension, wherein
the said powder is filled in to a device which allows the
reconstitution of said powder with a liquid vehicle just before
administration, comprises the step of: Mixing Temozolomide, one or
more diluent, one or more stabilizer, one or more glidant,
optionally one or more sweetener, optionally one or more flavoring
agent to obtain a blend. Dispersing suspending agent along with
stirring in solvent Optionally adding sweetener, preservative,
flavouring agent with solvent in the dispersion obtained in step b)
Making the final volume of liquid vehicle with water along with
stirring. Filling up the temozolomide powder blend of step a) and
liquid vehicle of step d) in dual chamber bottle device.
Description
RELATED APPLICATIONS
[0001] This application is related to Indian Provisional
Application No. 201921028629 filed on 16 Jul. 2019 and is
incorporated herein in its entirety.
FIELD OF THE INVENTION
[0002] The present invention relates to the stable pharmaceutical
composition of temozolomide for oral administration. The said
pharmaceutical composition is in the form of powder for oral
suspension, wherein the said powder is reconstituted with a liquid
vehicle just before administration. Further, the invention relates
to process for the preparation of said pharmaceutical composition
and its use thereof.
BACKGROUND OF THE INVENTION
[0003] Temozolomide is an alkylating agent and is chemically known
as 4-methyl-5-oxo-2,3,4,6,8-pentazabicyclo[4.3.0]
nona-2,7,9-triene-9-carboxamide. The empirical formula of
Temozolomide is C.sub.6H.sub.6N.sub.6O.sub.2 and the molecular
weight is 194.151 g/mol. The chemical structure of Temozolomide is
as shown below:
##STR00001##
[0004] Currently, Temozolomide capsules and powder for intravenous
injections are available under the brand name of Temodar.RTM. in
the US. Commonly, Temozolomide doses are between 5 mg to 250 mg in
oral and parenteral routes for adult patients.
[0005] Temozolomide is used for the treatment of newly diagnosed
glioblastoma multiforme and Refractory Anaplastic Astrocytoma.
Cancer is known to be a disease that reduces the quality of life of
the patients due to the course of the disease, symptoms and
complications; and also due to hard treatment methods and adverse
effects resulting from the treatment. Therefore, increasing patient
compliance to the treatment in both physical and psychological ways
is crucial for the success of the treatment. For instance, the
patient may have difficulty in swallowing due to psychological
causes, age, symptoms of the disease or adverse effects resulting
from the treatment; and may not be able to continue the treatment
properly. Further, Temozolomide is cytotoxic drug which require
specific precaution during its exposure. Non-compliance between the
patient and the treatment significantly affects the success of the
treatment of which each stage has vital importance.
[0006] The U.S. Pat. No. 5,260,291 discloses the Temozolomide
molecule and its use in the treatment of malignant neoplasms
including glioma.
[0007] WO2018/167627A1 discloses, in general, pharmaceutical
composition for oral suspension comprising alkylating
antineoplastic agent and pharmaceutically acceptable excipients
with improved stability. Notably, temozolomide undergoes hydrolytic
degradation, hence an oral suspension as disclosed in the said PCT
patent may have adverse effect on stability due to increased
hydrolytic degradation.
[0008] Particularly, no stability data is provided in the said PCT
patent.
[0009] Trisselel. al. determined the pharmaceutical acceptability
and chemical stability of temozolomide in two extemporaneously
compounded suspension formulations prepared from the capsules.
Temozolomide extemporaneously prepared as oral suspensions from
capsules found chemically stable for at least 60 days at 4.degree.
C.
[0010] Nygren et. al. had investigated the stability of
temozolomide in solutions prepared from the commercially available
powder for intravenous infusion. The study resulted that more than
90% of temozolomide remained intact after storage for 9 days at
room temperature (2.5 mg/mL) and 13 weeks at 5.degree. C. (1.25
mg/mL)
[0011] As temozolomide is a cytotoxic drug, the preparation of oral
suspensions from capsules or oral solutions from injection pose a
high risk for the dispenser or the health professional to directly
come in contact with the drug due to spillage of powder from the
capsule or liquid from the injection.
[0012] The currently marketed formulations are suitable for adults,
but they are not adopted for pediatric patients. Indeed, the
children find difficulty in swallowing the capsules, and the
intravenous administration is quite traumatic. This situation is
particularly critical for newborn babies as well as young children.
In addition, chemotherapy intravenous administration is not
appropriate for ambulatory treatments, wherein the children have to
take a daily dose over months.
[0013] From the prior art, it is observed that there are issues
with the stability of temozolomide when formulated in oral
suspension form. Further, due to cytotoxic effect of temozolomide,
precaution is required during the handling of temozolomide
formulation.
[0014] Thus, there is a need, in general, to provide stable
pharmaceutical composition of temozolomide, which remains stable
during the course of therapy and provides with increasing patient
compliance thereby optimizing therapeutic actions of
temozolomide.
Objects of the Invention
[0015] The primary object of the present invention is to provide a
stable oral pharmaceutical composition comprising temozolomide and
one or more pharmaceutically acceptable excipients, wherein the
said composition is in the form of a powder for oral
suspension.
[0016] Another object of the present invention is to provide a
stable oral pharmaceutical composition comprising temozolomide and
one or more pharmaceutically acceptable excipients, wherein the
said composition is in the form or a powder for oral suspension,
wherein the said powder is reconstituted with a liquid vehicle just
before administration.
[0017] Another object of the present invention is to provide a
stable oral pharmaceutical composition comprising temozolomide and
one or more pharmaceutically acceptable excipients, wherein the
said composition is in the form of a powder for oral suspension and
comprises of temozolomide, diluent, glidant, stabilizer and
optionally a sweetener and flavoring agent.
[0018] Another object of the present invention is to provide a
stable oral pharmaceutical composition comprising temozolomide and
one or more pharmaceutically acceptable excipients, wherein the
said composition is in the form of a powder for oral suspension,
wherein the said powder is reconstituted with a liquid vehicle just
before administration; wherein the said liquid vehicle comprises of
suspending agent, one or more solvent, and optionally a sweetener,
preservative and a flavoring agent.
[0019] Another object of the present invention is to provide a
stable oral pharmaceutical composition comprising temozolomide and
one or more pharmaceutically acceptable excipients, wherein the
said composition is in the form of a powder for oral suspension,
wherein the said powder is filled into a device which allows the
reconstitution of said powder with a liquid vehicle just before
administration.
[0020] Another object of the present invention is to provide
process for the preparation of a stable oral pharmaceutical
composition comprising temozolomide and one or more
pharmaceutically acceptable excipients, wherein the said
composition is in the form of a powder for oral suspension.
[0021] Another object of the present invention is to provide
process for the preparation of a stable oral pharmaceutical
composition comprising temozolomide and one or more
pharmaceutically acceptable excipients, wherein the said
composition is in the form of a powder for oral suspension, wherein
the said powder is filled in to a device which allows the
reconstitution of said powder with a liquid vehicle just before
administration.
[0022] Another object of the present invention is to provide a
stable oral pharmaceutical composition comprising temozolomide and
one or more pharmaceutically acceptable excipients, wherein the
said composition is in the form of a powder for oral suspension,
wherein the said powder is filled in to a device which allows the
reconstitution of the said powder and prevents the exposure of
cytotoxic effect of temozolomide.
[0023] Another object of the present invention is to provide a
stable oral pharmaceutical composition comprising temozolomide and
one or more pharmaceutically acceptable excipients, wherein the
said composition is in the form of a powder for oral suspension,
wherein the said powder is filled in to a device which allows the
reconstitution of the said powder and masks the bitter taste of
temozolomide.
[0024] Another object of the present invention is to provide a
stable oral pharmaceutical composition comprising temozolomide and
one or more pharmaceutically acceptable excipients, wherein the
said composition is in the form of a powder for oral suspension,
wherein the said suspension is used for administration to pediatric
patients.
[0025] Another object of the present invention is to provide a
stable oral pharmaceutical composition comprising temozolomide and
one or more pharmaceutically acceptable excipients, wherein the
said composition is in the form or a powder for oral suspension,
wherein the said composition does not have more than 5% (w/w) of
total impurity, more preferably does not have more than 3% of total
impurity of Temozolomide after being stored at specific storage
conditions.
SUMMARY OF THE INVENTION
[0026] The present invention provides a stable oral pharmaceutical
composition comprising temozolomide and one or more
pharmaceutically acceptable excipients, wherein the said
composition is in the form of a powder for oral suspension, wherein
the said powder is filled into a device which allows the
reconstitution of said powder with a liquid vehicle just before
administration. Further, the present invention also provides
process for the preparation of said pharmaceutical composition
comprising temozolomide according to the present invention, and
their use in treatment of patients in need thereof.
DETAILED DESCRIPTION
[0027] The detailed description and the examples provided herein
are exemplary and any modification or variation within the scope of
the invention will be apparent to a person skilled in the art.
Further, unless otherwise defined, all the technical and scientific
terms used herein shall bear the meaning as understood by a person
who is ordinarily skilled in the art.
[0028] The present invention provides a stable oral pharmaceutical
composition comprising temozolomide and one or more
pharmaceutically acceptable excipients, wherein the said
composition is in the form of a powder for oral suspension, wherein
the said powder is filled into a device which allows the
reconstitution of said powder with a liquid vehicle just before
administration. Further, the present invention also provides
process for the preparation of said pharmaceutical composition
comprising temozolomide according to the present invention, and
their use in treatment of newly diagnosed glioblastoma multiforme
and Refractory Anaplastic Astrocytoma in patients need thereof.
[0029] The term "Temozolomide" used throughout the specification
refers to their pharmaceutically acceptable salt, pharmaceutically
acceptable solvates, pharmaceutically acceptable hydrates,
pharmaceutically acceptable enantiomers, pharmaceutically
acceptable derivatives, pharmaceutically acceptable polymorphs and
pharmaceutically acceptable pro-drugs thereof, wherein the amount
of temozolomide is present from 30% w/w to 60% w/w of total
composition which is in the powder form of preparation. Further
after the reconstitution the amount of temozolomide is present from
5 mg/mL to 50 mg/mL of total composition before administration.
[0030] The term "pharmaceutical composition" for the purpose of the
invention, means a composition in the form of powder for the
preparation of oral suspension, wherein the said powder can be
reconstituted with a liquid vehicle just before administration.
[0031] The said pharmaceutical composition comprises of
temozolomide and one of more pharmaceutically acceptable
excipients.
[0032] The term "pharmaceutically acceptable" means salt, carriers,
excipients, and other formulation ingredients that are compatible
with all other pharmaceutical ingredients of a composition and are
not deleterious to an individual treated with composition.
[0033] The term "specific storage conditions" as used throughout
the specification, refers to the pharmaceutical composition of
present invention stored for at least one month, more preferably
six months at 40.degree. C./75% RH.
[0034] The composition of temozolomide is reconstituted with liquid
vehicle to obtain suspension of temozolomide just before
administration, wherein the said suspension of temozolomide remains
stable for at least 7 days at 25.degree. C. and 60% RH and for at
least 14 days at 0.degree. C. to 8.degree. C.
[0035] The term "total impurities" of temozolomide as used
throughout the specification, refers to identified or unidentified
degradation product or impurity structurally related with
temozolomide which are arising from a manufacturing process or
during storage of material.
[0036] The term "unspecified impurity" of temozolomide as used
throughout the specification refers to can be either any
unidentified impurity which is arising from a manufacturing process
or during storage of material at specific storage conditions
[0037] The term "stable" as used throughout the specification,
refers to oral pharmaceutical composition of temozolomide and one
or more pharmaceutically acceptable excipients, wherein the said
composition is in the form of powder and does not contain more than
5% (w/w) of total impurity. The stable powder for oral suspension
refers to a pharmaceutical composition in which the active
ingredient, temozolomide, is present in an amount of at least 90%
of the original label specified amount for each such ingredient
stored at 40.degree. C./75% RH for at least one month, more
preferably six months.
[0038] The term "powder" as used throughout the specification,
refers to either a blend of temozolomide and one or more
pharmaceutically acceptable excipients, or granules prepared by
mixing of one or more pharmaceutically acceptable excipients or any
of the conventional granulation techniques such as wet granulation,
dry granulation and direct compaction. The said conventional
granulation techniques are well-known in the literature.
[0039] The term "stabilizer" used throughout the specification
refers to any chemical or agents inhibit the degradation of
Temozolomide by inhibiting the formation of a degradation product.
The preferred stabilizer used according to the present invention is
an organic acid such as ascorbic acid and its derivatives, malic
acid, isoascorbic acid, citric acid, tartaric acid, and mixtures
thereof.
[0040] The term "device" as used throughout the specification,
refers to the packaging container comprising two components. In one
embodiment, a device comprises a dual-component packaging
comprising: (a) a stable oral pharmaceutical composition comprising
temozolomide and one or more pharmaceutically acceptable excipients
in the first component, (b) a liquid vehicle in the second
component. In another embodiment, the device can be a dual-chamber
packaging comprising: (a) stable oral pharmaceutical composition
comprising temozolomide and one or more pharmaceutically acceptable
excipients, (b) a liquid vehicle, wherein the said composition can
be reconstituted with the liquid vehicle in the said device just
before administration.
[0041] Preferably, the said device comprises a dual-chamber bottle
comprising: (a) a stable oral pharmaceutical composition comprising
temozolomide and one or more pharmaceutically acceptable excipients
in the first chamber, (b) a liquid vehicle in the second chamber,
wherein the said composition can be reconstituted with the liquid
vehicle in the said device just before administration. The
dual-chamber bottle comprises first chamber in the bottle cap and
the liquid vehicle in the bottle chamber. The dual-chamber bottle
of the present invention is designed such that the pharmaceutical
composition is filled in the bottle cap chamber and is released
into liquid vehicle chamber of the bottle by applying pressure and
tightening of the cap, and hence the pharmaceutical composition can
be reconstituted with liquid vehicle in the said bottle chamber
prior to administration.
[0042] One of the embodiments of the present invention is to
provide a stable oral pharmaceutical composition comprising
temozolomide and one or more pharmaceutically acceptable
excipients, wherein the said composition is in the form of a powder
for oral suspension.
[0043] Another embodiment of the present invention is to provide a
stable oral pharmaceutical composition comprising temozolomide and
one or more pharmaceutically acceptable excipients, wherein the
said composition is in the form or a powder for oral suspension,
wherein the said powder is reconstituted with a liquid vehicle just
before administration.
[0044] Another embodiment of the present invention is to provide a
stable oral pharmaceutical composition comprising temozolomide and
one or more pharmaceutically acceptable excipients, wherein amount
of temozolomide in the said stable powder for oral suspension is in
the range from 5 mg/ml to 50 mg/ml, more preferably from 10 mg/ml
to 30 mg/ml.
[0045] Yet another embodiment of the present invention is to
provide a stable oral pharmaceutical composition comprising
temozolomide and one or more pharmaceutically acceptable
excipients, wherein the said composition is in the form of a powder
for oral suspension and comprises of temozolomide, diluent,
glidant, stabilizer, and optionally a sweetener and flavoring
agent.
[0046] Yet another embodiment of the present invention is to
provide a stable oral pharmaceutical composition comprising
temozolomide and one or more pharmaceutically acceptable
excipients, wherein the said composition is in the form or a powder
for oral suspension, wherein the said powder is reconstituted with
a liquid vehicle just before administration; wherein the said
liquid vehicle comprises of suspending agent, one or more solvent,
and optionally a sweetener, preservative and a flavoring agent.
[0047] Yet another embodiment of the present invention is to
provide a stable oral pharmaceutical composition comprising
temozolomide and one or more pharmaceutically acceptable
excipients, wherein the said composition is in the form of a powder
for oral suspension, wherein the said powder is filled into a
device which allows the reconstitution of said powder with a liquid
vehicle just before administration.
[0048] Yet another embodiment of the present invention is to
provide process for the preparation of a stable oral pharmaceutical
composition comprising temozolomide and one or more
pharmaceutically acceptable excipients, wherein the said
composition is in the form of a powder for oral suspension.
[0049] Yet another embodiment of the present invention is to
provide process for the preparation of a stable oral pharmaceutical
composition comprising temozolomide and one or more
pharmaceutically acceptable excipients, wherein the said
composition is in the form of a powder for oral suspension, wherein
the said powder is filled in to a device which allows the
reconstitution of said powder with a liquid vehicle just before
administration.
[0050] Yet another embodiment of the present invention is to
provide a stable oral pharmaceutical composition comprising
temozolomide and one or more pharmaceutically acceptable
excipients, wherein the said composition is in the form of a powder
for oral suspension, wherein the said powder is filled in to a
device which allows the reconstitution of the said powder and
prevents the exposure of cytotoxic effect of temozolomide.
[0051] Yet another embodiment of the present invention is to
provide a stable oral pharmaceutical composition comprising
temozolomide and one or more pharmaceutically acceptable
excipients, wherein the said composition is in the form of a powder
for oral suspension, wherein the said powder is filled in to a
device which allows the reconstitution of the said powder and masks
the bitter taste of temozolomide.
[0052] Yet another embodiment of the present invention is to
provide a stable oral pharmaceutical composition comprising
temozolomide and one or more pharmaceutically acceptable
excipients, wherein the said composition is in the form of a powder
for oral suspension, wherein the said suspension is used for
administration to pediatric patients.
[0053] Yet another embodiment of the present invention is to
provide a stable oral pharmaceutical composition comprising
temozolomide and one or more pharmaceutically acceptable
excipients, wherein the said composition is in the form or a powder
for oral suspension, wherein the said composition does not have
more than 5% (w/w) of total impurity, more preferably does not have
more than 3% of total impurity of temozolomide after being stored
at specific storage conditions.
[0054] According to the embodiment of the present invention, the
pharmaceutical composition of the present invention comprises of a
diluent, wherein the said diluent can be selected form the group
comprising of lactose, calcium phosphate, calcium sulfate, calcium
carbonate, mannitol, xylitol, sucrose, maltose, fructose, dextrose,
and maltodextrin or mixtures thereof. The diluents can be present
in a concentration of from about 30% to about 60% by weight of the
total weight of the composition.
[0055] In one of the preferred embodiments, the said pharmaceutical
composition of the present invention comprises preferably mannitol
as a diluent. Further, mannitol may have a dual role as a diluent
and may also act as a sweetener. Also, mannitol is present in a
ratio equal to or less than as compared to temozolomide.
[0056] According to the embodiment of the present invention, the
pharmaceutical composition of the present invention comprises of a
stabilizer, wherein the said stabilizer is preferably an organic
acid. The said stabilizer is present in a concentration of at least
1% w/w to 5% w/w of the said pharmaceutical composition. More
preferably, the said stabilizer is tartaric acid.
[0057] According to the embodiment of the present invention, the
pharmaceutical composition of the present invention comprises of a
glidant, wherein the said glidant is selected from a group
comprising of colloidal silicon dioxide, magnesium silicate,
starch, talc, tribasic calcium phosphate, stearic acid, palmitic
acid or mixtures thereof. The said glidant is present in a
concentration of at least 0.5% w/w to 2% w/w of the said
pharmaceutical composition. More preferably, the said glidant is
colloidal silicon dioxide.
[0058] According to the embodiment of the present invention, the
liquid vehicle of the present invention comprises of suspending
agent, wherein the said suspending agent is selected from a group
comprising of carrageenan, cellulose ether, xanthan gum, sodium
alginate, microcrystalline cellulose. The suspending agent helps in
appropriately suspending the ingredients of the suspension and
prevents formation of a cake at the bottom of the device. More
preferably, the said suspending agent is microcrystalline
cellulose. The said suspending agent is present in a concentration
of at least 0.5% w/w to 10% w/w of the said pharmaceutical
composition
[0059] According to the embodiment of the present invention, the
liquid vehicle of the present invention comprises of preservatives,
wherein the said preservatives is selected from a group comprising
of Alcohol, Benzalkonium Chloride, Benzethonium Chloride, Benzoic
Acid, Benzyl Alcohol, Boric Acid, Bronopol, Butylene Glycol,
Butylparaben, Calcium Acetate, Calcium Chloride, Calcium Lactate,
Cetrimide, CetylpyridiniumChloride, Chlorhexidine, Chlorobutanol,
Chlorocresol, Chloroxylenol, Citric Acid Monohydrate, Cresol,
Glycerin, Hexetidine, Imidurea, Methylparaben, Monothioglycerol,
Phenol, Phenoxyethanol, Phenylethyl Alcohol, Phenylmercuric
Acetate, Phenylmercuric Borate, Phenylmercuric Nitrate, Potassium
Benzoate, PotassiumMetabisulfite, Potassium Sorbate, Propionic
Acid, Propylene Glycol, Propylparaben, Propylparaben Sodium,
SodiumAcetate, Sodium Benzoate, Sodium Borate, Sodium Lactate,
Sodium Metabisulfite, Sodium Propionate, Sodium Sulfite, Sorbic
Acid, Sulfur Dioxide, Thimerosal. More preferably, the said
preservatives is methyl paraben and propyl paraben. The said
preservative is present in a concentration of at least 0.5% w/w to
5% w/w of the said pharmaceutical composition.
[0060] According to the embodiment of the present invention, the
liquid vehicle of the present invention comprises of solvent
selected from a group of water, hydro-alcoholic, polyhydric
alcohols. More preferably, the solvent selected are sorbitol,
glycerol, water and mixtures thereof. Sorbitol and glycerol provide
dual function as a solvent as well as a sweetener, which helps in
masking the taste of temozolomide.
[0061] According to the embodiment of the present invention, the
sweetener can be selected form the group comprising of alitame,
acesulfame potassium, aspartame, D-tryptophan, dextrose,
erythritol, fructose, galactose, glycerol, glycyrrhizin, glucose,
isomalt, xylitol, xylose, lactitol, lactose, levulose, maltitol,
maltodextrin, maltol, maltose, mannitol, corn syrup,
neohesperidindihydrochalcone, neotame, saccharin, siclamate,
sorbitol, sucralose, sucrose, tagatose, taumatin and trehalose. The
said sweetener is present in a concentration of at least 0.1% w/w
to 10% w/w of the said pharmaceutical composition.
[0062] According to the embodiment of the present invention, the
flavoring agent can be selected form the group comprising of
essential oils including peppermint oil, orange oil, lemon oil or
can be selected from fruit flavors. The flavoring agent can be
present in a concentration of from about 0.1% w/w to about 10% w/w
of said pharmaceutical composition.
[0063] In yet another embodiment, the present invention is to
provide a stable pharmaceutical composition comprising temozolomide
and one or more pharmaceutically acceptable excipients, wherein the
said composition is in the form of a powder for oral suspension,
wherein the said powder is reconstituted with a liquid vehicle just
before administration; and is used for the treatment of newly
diagnosed glioblastoma multiforme and Refractory Anaplastic
Astrocytoma in adult as well as pediatric patients.
[0064] According to present invention, the process for the
preparation of the pharmaceutical composition comprising
temozolomide and one or more pharmaceutical acceptable excipients,
comprises the following steps: [0065] (a) Mixing Temozolomide, one
or more diluent, one or more stabilizer, one or more glidant to
obtain a blend. [0066] (b) Optionally adding sweetener and
flavoring agent to the blend obtained in step a) to obtain the
pharmaceutical composition of temozolomide in powder form for oral
suspension.
[0067] According to present invention, the process for the
preparation of liquid vehicle utilized for the reconstitution of
pharmaceutical composition of temozolomide for preparation of oral
suspension is as follows: [0068] (a) Dispersing/dissolving the
suspending agent along with stirring in solvent. [0069] (b)
Optionally adding preservative, sweetener and flavoring agent in
step a) along with stirring. [0070] (c) Making up the volume with
water along with stirring.
[0071] According to present invention, process for the preparation
of a stable oral pharmaceutical composition comprising temozolomide
and one or more pharmaceutically acceptable excipients, wherein the
said composition is in the form of a powder for oral suspension,
wherein the said powder is filled in to a device which allows the
reconstitution of said powder with a liquid vehicle just before
administration, comprises the step of:
[0072] For pharmaceutical composition of temozolomide: [0073] (a)
Mixing Temozolomide, one or more diluent, one or more stabilizer,
one or more glidant to obtain a blend. [0074] (b) Optionally adding
sweetener and flavoring agent to the blend obtained in step a) to
obtain the pharmaceutical composition of temozolomide in powder
form for oral suspension.
[0075] For liquid vehicle: [0076] (a) Dispersing or dissolving the
suspending agent along with stiffing in solvent. [0077] (b)
Optionally adding preservative, sweetener and flavoring agent in
step a) along with stirring. [0078] (c) Making up the volume with
water along with stiffing.
[0079] In yet another embodiment, the present invention is to
provide a stable pharmaceutical composition comprising temozolomide
and one or more pharmaceutically acceptable excipients, wherein
said composition is reconstituted with liquid vehicle to obtain
suspension of temozolomide just before administration, wherein the
said reconstituted suspension of temozolomide remains stable for at
least 7 days at 25.degree. C. and 60% RH and for at least 14 days
at 0.degree. C. to 8.degree. C.
[0080] The pharmaceutical composition of temozolomide and liquid
vehicle are filled in a device. Further, the device allows the
reconstitution of pharmaceutical composition of temozolomide and
liquid vehicle just before administration.
[0081] In yet another embodiment, the present invention is to
provide a stable pharmaceutical composition comprising temozolomide
and one or more pharmaceutically acceptable excipients, wherein the
said composition is in the form of a powder for oral suspension,
wherein the said powder is reconstituted with a liquid vehicle just
before administration; and the said composition can be used as
single dose or multi dose administration formulation in adult as
well as pediatric patients.
[0082] In order to further illustrate the present invention, the
following examples are provided for the purpose of clarity of
understanding. However, it is not intended in any way to limit the
scope of present invention and it is readily apparent to those of
ordinary skill in the art in light of the teachings of this
invention that certain changes and modifications may be made
thereto without departing from the scope of the invention.
EXAMPLE--1: General Composition
TABLE-US-00001 [0083] Ingredient % w/w Temozolomide 30-60% Diluent
30-60% Stabilizer 1-5% Glidant 0.5-2% Sweetener (Optional) 0.1-10%
Flavouring agent (Optional) 0.1-10%
[0084] Manufacturing Process:
[0085] (a) Mixing Temozolomide, one or more diluent, one or more
stabilizer, one or more glidant to obtain a blend.
[0086] (b) Optionally adding sweetener and flavoring agent to the
blend obtained in step a) to obtain the pharmaceutical composition
of Temozolomide in powder form for oral suspension.
EXAMPLE 2: Pharmaceutical Composition of Temozolomide
TABLE-US-00002 [0087] Strengths 150 mg/ 300 mg/ Ingredients 7.5 ml
15 ml Temozolomide 150 300 Mannitol (Perlitol SD 100) 135.9 271.8
Colloidal Silicon dioxide 1.5 3 Tartaric acid 10.5 21 Sucralose 1.5
3 Flavor (forest Berry) 0.6 1.2 Total Blend 300 600 Liquid Vehicle
Microcrystalline cellulose 112.5 225 Glycerol 1125 2250 Sorbitol
3375 6750 Water Qs to 7.5 ml Qs to 15 ml Packaging component Dual
Chamber PET bottle 1 No. 1 No. Powder filling Kit 1 No. 1 No.
[0088] Manufacturing Process:
[0089] (a) Mixing Temozolomide, mannitol, colloidal silicon
dioxide, tartaric acid to obtain a blend.
[0090] (b) Adding sucralose and forest berry flavors to the blend
obtained in step a) to obtain the final blend of temozolomide
powder.
[0091] (c) Dispersing microcrystalline cellulose along with
stirring in glycerol.
[0092] (d) Adding the sorbitol in the dispersion obtained in step
c)
[0093] (e) Making the final volume of liquid vehicle with water
along with stiffing.
[0094] (f) Filling up the temozolomide powder blend of step b) and
liquid vehicle of step e) in dual chamber bottle device to final
composition of oral suspension.
[0095] STABILITY STUDY:
TABLE-US-00003 TABLE 1 Stability data of 150 mg/7.5 ml imatinib
powder for solution of example 2 at condition of 40.degree. C./75%
RH. Any Stability unspecified Total stations impurity impurity
Initial ND 0.035 3 months ND 0.135
[0096] The above data shows a total impurity not more than 5% of
temozolomide in the formulation, indicative of stability of
Temozolomide powder for oral suspension in the drug product.
EXAMPLE--3: Pharmaceutical Composition of Temozolomide (without
Preservative--Unit Dose)
TABLE-US-00004 [0097] Strengths 150 mg/ 300 mg/ Ingredients 7.5 ml
15 ml Temozolomide 150 300 Mannitol (Perlitol SD 100) 138 276
Colloidal silicon di oxide 1.5 3 Tartaric acid 10.5 21 Liquid
Vehicle Microcrystalline cellulose 112.5 225 Glycerol 1125 2250
Sorbitol 3375 6750 Sucralose 1.5 3 Flavor (forest Berry) 0.6 1.2
Water Qs to 7.5 ml Qs to 15 ml Packaging component Dual Chamber PET
bottle 1 No. 1 No. Powder filling Kit 1 No. 1 No.
[0098] Manufacturing Process:
[0099] (a) Mixing Temozolomide, mannitol, colloidal silicon
dioxide, tartaric acid to obtain a blend of Temozolomide
powder.
[0100] (b) Dispersing microcrystalline cellulose along with
stirring in glycerol.
[0101] (c) Adding sorbitol, sucralose and forest berry flavors in
the dispersion obtained in step b)
[0102] (d) Making the final volume of liquid vehicle with water
along with stiffing.
[0103] (e) Filling up the temozolomide powder blend of step a) and
liquid vehicle of step d) in dual chamber bottle device.
[0104] STABILITY STUDY:
TABLE-US-00005 TABLE 2 Stability data of 150 mg/7.5 ml Temozolomide
powder of example 3 at condition of 40.degree. C./75% RH (Without
preservative). Related Stability 30 60 90 180 substances Limits
Initial Days Days Days Days Unspecified NMT ND ND ND ND ND Impurity
0.2% Total NMT 0.063 0.100 0.045 0.124 0.537 Impurities 5% Assay
90-110% 100.7 98.3 100.0 99.5 100.7
[0105] The above data shows a total impurity not more than 5% of
Temozolomide in the formulation and the assay of Temozolomide is in
range of 90-110%, indicative of stability of Temozolomide
powder.
TABLE-US-00006 TABLE 3 Stability data of reconstituted 150 mg/7.5
ml Temozolomide powder for suspension of example 3 (Without
preservative) Related Stability 25.degree. C./60% RH 2-8.degree. C.
substances Limits Initial 1 Days 3 Days 5 Days 7 Days 3 Days 7 Days
14 Days Unspecified NMT ND 0.056 0.067 0.070 0.115 ND ND ND
Impurity 0.2% Total NMT 0.045 0.289 0.749 1.124 1.597 0.091 0.133
0.154 Impurities 5%
[0106] The above data shows a total impurity not more than 5% of
Temozolomide in the formulation indicative of stability of
reconstituted Temozolomide powder for suspension.
[0107] EXAMPLE--4: Pharmaceutical Composition of Temozolomide (With
Preservative--Unit Dose)
TABLE-US-00007 Strengths 150 mg/ 300 mg/ Ingredients 7.5 ml 15 ml
Temozolomide 150 300 Mannitol (Perlitol SD 100) 138 271.8 Colloidal
Silicon dioxide 1.5 3 Tartaric acid 10.5 21 Total Blend 300 600
Liquid Vehicle Microcrystalline cellulose 112.5 225 Glycerol 1125
2250 Sorbitol 1700 3400 Sucralose 1.50 3 Flavor (forest Berry) 0.60
1.2 Methyl paraben 9.75 19.50 Propyl paraben 2.25 4.50 Water Qs to
7.5 ml Qs to 15 ml Packaging component Dual Chamber PET bottle 1
No. 1 No. Powder filling Kit 1 No. 1 No.
[0108] Manufacturing Process:
[0109] (a) Mixing Temozolomide, mannitol, colloidal silicon
dioxide, tartaric acid to obtain a blend.
[0110] (b) Dispersing microcrystalline cellulose along with
stiffing in glycerol.
[0111] (c) Adding the sorbitol, sucralose, methyl paraben, propyl
paraben and flavouring agent in the dispersion obtained in step
b)
[0112] (d) Making the final volume of liquid vehicle with water
along with stiffing.
[0113] (e) Filling up the temozolomide powder blend of step a) and
liquid vehicle of step d) in dual chamber bottle device.
[0114] STABILITY STUDY:
TABLE-US-00008 TABLE 4 Stability data of reconstituted 150 mg/7.5
ml Temozolomide powder for suspension of example 4 at condition of
40.degree. C./75% RH (With preservative). Related Stability
substances Limits Initial 30 Days 60 Days 90 Days Unspecified NMT
0.2% ND ND ND ND Impurity Total NMT 5% 0.041 0.080 0.074 0.157
Impurities Assay 90-110% 96.4 98.0 97.6 97.3
[0115] The above data shows a total impurity not more than 5% of
Temozolomide in the formulation, and the assay of Temozolomide is
in range of 90-110%, indicative of stability of Temozolomide powder
for suspension in the drug product.
[0116] The stability data as mentioned above indicate that the
pharmaceutical composition comprising temozolomide or its
pharmaceutically acceptable salt thereof and one or more
pharmaceutical acceptable excipients in powder form reconstituted
with a liquid vehicle just before use are stable.
EXAMPLE--5: Pharmaceutical Composition of Temozolomide (With
Preservative--Multi-Dose)
TABLE-US-00009 [0117] Strengths 100mg/5 mL; 100mg/5 mL; Ingredients
40 mL 80 mL Temozolomide 800.00 1600 Mannitol (Perlitol SD 100)
736.00 1472 Colloidal Silicon dioxide 8.00 16 Tartaric acid 56.00
112 Total Blend 1600 3200 Liquid Vehicle Microcrystalline cellulose
600.00 1200 Glycerol 6000.00 12000 Sorbitol 9066.67 18133.34
Sucralose 8.00 16 Flavor (forest Berry) 3.20 6.4 Methyl paraben
52.00 104 Propyl paraben 12.00 24 Water Qs to 40 ml Qs to 80 ml
Packaging component Dual Chamber PET bottle 1 No. 1 No. Powder
filling Kit 1 No. 1 No.
[0118] The oral compositions of the present invention can be
administered as multi-dose formulations to pediatrics patients.
* * * * *